WO2014093604A1 - Détermination de la localisation d'une charge bactérienne dans les poumons - Google Patents

Détermination de la localisation d'une charge bactérienne dans les poumons Download PDF

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WO2014093604A1
WO2014093604A1 PCT/US2013/074629 US2013074629W WO2014093604A1 WO 2014093604 A1 WO2014093604 A1 WO 2014093604A1 US 2013074629 W US2013074629 W US 2013074629W WO 2014093604 A1 WO2014093604 A1 WO 2014093604A1
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samples
sample
isotopically
labeled compound
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Elizabeth A. PERKETT
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Avisa Diagnostics Inc
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Avisa Pharma Inc
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Priority to BR112015013826A priority Critical patent/BR112015013826A2/pt
Priority to HK16102961.3A priority patent/HK1215069A1/zh
Priority to CN201380064969.9A priority patent/CN104903725A/zh
Priority to EP13814762.4A priority patent/EP2932262A1/fr
Priority to RU2015128043A priority patent/RU2015128043A/ru
Priority to AU2013359271A priority patent/AU2013359271A1/en
Priority to CA2893821A priority patent/CA2893821A1/fr
Priority to JP2015547534A priority patent/JP2016504581A/ja
Publication of WO2014093604A1 publication Critical patent/WO2014093604A1/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/39—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using tunable lasers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/314—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry with comparison of measurements at specific and non-specific wavelengths
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/42—Absorption spectrometry; Double beam spectrometry; Flicker spectrometry; Reflection spectrometry
    • G01J3/433—Modulation spectrometry; Derivative spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/39—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using tunable lasers
    • G01N2021/396—Type of laser source
    • G01N2021/399—Diode laser
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3504—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing gases, e.g. multi-gas analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G01N2201/022—Casings
    • G01N2201/0221—Portable; cableless; compact; hand-held

Definitions

  • the invention is directed to methods of detecting the presence and location of bacterial load in the lungs of a subject.
  • Bacteria are naturally present in the lungs and if the bacterial load remains low, these bacteria will not adversely affect normal respiratory function. The presence of bacteria is called colonization, rather than infection. When the bacterial load increases in the upper airway, it may still be colonization and is generally not life threatening, but increased colonization may precede infection so measures may be started to decrease colonization before severe infection occurs. Increased colonization can be treated using non-aggressive methods, for example, by increasing airway clearance or by administering oral or inhaled broad-spectrum antibiotics.
  • the present invention is directed to methods for determining the presence or absence and location of a bacterial load in the respiratory system of a subject comprising:
  • Figure 1 is a plan view of an exemplary laser absorbance device for use in accordance with some embodiments of this invention.
  • Figure 2 illustrates a preferred jump scanning regime.
  • 13 C-isotopically-labeled compound that produces 13 C0 2 upon bacterial metabolism.
  • Samples of exhaled breath are then collected and analyzed to determine the isotopic ratio of 13 C0 2 to 12 C0 2 present in the samples.
  • An increase in the isotopic ratio of 13 C0 2 to 12 C0 2 in the exhaled breath samples, as compared to a control sample, is indicative of a bacterial lung infection. See, e.g.,
  • the present invention is directed to methods for determining the location of increased bacterial load in the lung. Any bacteria that can convert the 13 C- isotopically-labeled compounds of the invention into 13 C0 2 can be detected using the methods of the invention. Examples of such bacteria include Pseudomonas aeruginosa, Staphylococcus aureus, Mycobacterium tuberculosis, Acenitobacter baumannii, Klebsiella pneumonia,
  • Francisella tularenis Francisella tularenis, Proteus mirabilis, and Aspergillus species.
  • An entire exhaled breath sample from a subject will include air from both the upper and lower airways. Air from the lower airways has a higher concentration of carbon dioxide than air from the upper airways. It is generally understood that air from the lower airways of a healthy adult has a pressure of CO 2 of about 40 mm Hg. John F. Murray, The
  • Active pressure sensing can also be used to determine from where in the lung an exhaled breath originated. See, e.g., WO 2008/060165; U.S. 7,547,285.
  • passive pressure sensing can be used to channel and isolate samples from the upper and lower respiratory tract. See, e.g., Bio-VOCTM Breath Sampler (Markes International Limited, United Kingdom); U.S. 3,734,692; WO 1994/018885; WO 2003/049595; and WO 2004/032727.
  • Determination of the origin of an exhaled breath sample can also be achieved by measuring the temperature of the breath sample. See, e.g., U.S. 4,248,245. Alternatively, exhaled breath is monitored using transthoracic impedance methods, which are known in the art.
  • the methods of the invention include administering to the subject, an effective amount of a 13 C-isotopically-labeled compound that produces 13 C02 upon bacterial metabolism.
  • a 13 C-isotopically-labeled compound that produces 13 C02 upon bacterial metabolism.
  • exemplary examples of such compounds include isotopically labeled urea, isotopically labeled glycine, isotopically labeled citrulline, or a mixture thereof.
  • Administration of the 13 C- isotopically-labeled compound can be achieved by any known means. Preferred methods of administration include inhalation and ingestion. Administration via injection, i.e., intramuscular, subcutaneous, peritoneal, and intradermal injection, is also within the scope of the invention.
  • the 13 C-isotopically-labeled compound is administered to a specific area of the respiratory tract.
  • the 13 C-isotopically-labeled compound is delivered to the lower regions of the lungs, i.e., alveolar regions.
  • the 13 C-isotopically-labeled compound is delivered to the upper regions of the lungs.
  • the 13 C-isotopically-labeled compound is delivered to the bronchial areas of the lungs.
  • the 13 C-isotopically-labeled compound is delivered to peripheral areas of the lungs.
  • one or more exhaled breath samples from the subject can be collected before administration of the 13 C-isotopically-labeled compound.
  • Such samples can be used as control samples in the methods of the invention.
  • the control samples can include the isotopic ratio of 13 C0 2 to 12 C0 2 present in exhaled breath of a population that has not been administered the 13 C-isotopically-labeled compound.
  • a plurality of samples of exhaled breath are collected from the subject.
  • a “suitable time period” refers to the length of time required for the compound to be converted to carbon dioxide by a bacteria.
  • the samples are collected after no more than 40-70 minutes following administration.
  • the time required by the subject to complete a substantially complete exhalation can be evaluated.
  • the subject's breathing patterns can also be evaluated. Those evaluations can be used to, for example, determine preselected time periods during exhalation for sampling.
  • Samples can be collected in any vessel suitable for containing samples of exhaled breath, for example, a bag or vial. Samples may also be directly exhaled into the device by using a suitable mouthpiece. Samples can also be directed exhaled into the sample chamber of a detection apparatus device by being collected using a nasal cannula from a suitable port on other respiratory equipment, for example, a ventilator.
  • At least one of the exhaled breath samples will be from the upper respiratory tract and at least one of the exhaled breath samples will be from the lower respiratory tract of the subject.
  • the skilled person can identify the origin of the exhaled breath sample by determining the relative carbon dioxide concentration of the sample. A higher carbon dioxide concentration is indicative of the sample originating from the lower airways. A lower carbon dioxide concentration is indicative of the sample originating from the upper airways.
  • the skilled person can correlate the origin of the exhaled breath sample to the point in time of sample collection.
  • a sample collected at or near the beginning of the entire exhalation will have originated from the upper airways.
  • a sample collected at or near the end of the entire exhalation will have originated from the lower airways.
  • the origin of the exhaled breath can also be determined using any of the methods known in the art, such as, for example, capnography, active pressure sending, passive pressure sensing, temperature sensing, and transthoracic impedance.
  • the samples are analyzed to determine the isotopic ratio of 13 C0 2 to 12 C0 2 in the samples.
  • the skilled person can determine whether there is an increase in bacterial load and whether that increase is in the upper or lower airways.
  • the sample is conducted to a sample chamber of a detection apparatus.
  • a laser light source of the detection apparatus is actuated to emit one or more of the wavelength pairs 2054.37 and 2052.42; 2054.96 and 2051.67; or 2760.53 and 2760.08 nanometers.
  • the laser light thus actuated is directed through the sample in the sample chamber to impinge upon a detector for such wavelengths.
  • the isotopic ratio of 13 C0 2 to 12 C0 2 present in the sample can then be ascertained.
  • a graph or curve may be generated showing the ratio of 13 C0 2 to 12 C0 2 in the breath of the tested subject as a function of time.
  • a curve showing an increase in the ratio of 13 C0 2 to 12 C0 2 over time is evidence of the existence of a bacterial infection.
  • the concentrations or amounts (ratio) of 13 C0 2 to 12 C0 2 is compared to a standard concentration (ratio) of 13 C0 2 to 12 C0 2 in a healthy subject and a curve is conveniently generated. From the curve, the presence or absence of increased bacterial load may be determined or diagnosed directly. Other methods for comparing the output ratio to ratios expected from healthy subjects may also be employed.
  • a curve may be fitted to these measured
  • concentrations and is then analyzed, preferably by determining the rate of rise of the curve.
  • rate indicates the level of activity of bacterial load in the subject, which can be used to diagnose the presence and extent of bacterial load in the subject.
  • This same approach may be used, with modification, to determine the effectiveness of therapy and the prognosis for inhibition and/or a cure of infection or colonization.
  • an increase in the ratio of 13 C0 2 to 12 C0 2 in the exhaled breath samples obtained after inhalation of the 13 C-isotopically labeled compound to the isotopic ratio of 13 C0 2 to 12 C0 2 in the exhaled breath sample obtained from the subject prior to the inhalation of the 13 C-isotopically labeled compound indicates the presence a bacterial load.
  • Such treatments may include, for example, administering therapeutic agents.
  • agents include, for example, antibiotics such as broad spectrum, intravenous antibiotics.
  • Detection apparatuses useful in the present invention will include a sample chamber, into which breath samples can be conducted. These devices will also include a laser light source actuated to emit one or more of the wavelength pairs 2054.37 and 2052.42; 2054.96 and 2051.67; or 2760.53 and 2760.08 nanometers. These devices will also include a detector for detection of one or more of the wavelength pairs.
  • the detection apparatuses useful in the present invention can include small, extremely low power, near infrared diode lasers to attain field portable, battery operated 5 13 C0 2 measurement instruments with high degrees of accuracy and sensitivity. These devices and the methodologies which employ them may be used to determine 5 13 C0 2 in exhaled breath samples of subjects having, or suspected of having, a bacterial colonization or infection.
  • Preferred detection apparatuses will analyze carbon isotope ratios in exhaled carbon dioxide samples without being adversely affected by temperature changes.
  • the accuracy and precision of measuring carbon dioxide isotope ratios can be affected by changes in the ground state population of carbon dioxide.
  • the origins of the isotopic differences in samples may be diverse and are not the subject of the present invention. Rather, it is recognized that ascertaining the value of the isotopic ratio is inherently important and commercially useful.
  • Optical absorption spectroscopy is based on the well-known Beer-Lambert Law. Gas concentrations are determined by measuring the change in the laser beam intensity, I 0 , due to optical absorption of the beam by a sample of the gas. If a sample cell is used for the analysis, such that the path length of the beam and inherent characteristics of the measuring device are constant, absorbance measurements allow calculation of the gas number density, n, or gas concentration.
  • Gas phase diode laser absorption measurements interrogate individual absorption lines of gas molecules. These absorption lines correspond to the transition of the gas molecule, e.g. carbon dioxide, from a ground energy state to a higher excited energy state by absorption of a photon of light. The lines are typically quite narrow at reduced sample gas pressure thereby permitting selective detection of a gas in the presence of other background gases such as water vapor.
  • the isotopes of CO 2 have distinct absorption lines that occur at shifted wavelengths with respect to each other due to the mass difference between 12 C and 13 C.
  • Absorbance measurements are affected by the gas temperature and the magnitude of this temperature sensitivity varies depending on absorption line selection and the total ground state energy of the optical transition.
  • a collection of molecules at room temperature is distributed over many discrete molecular energy states that vary in total energy according to how fast the molecules rotate and vibrate. That is, the ground state molecular population is distributed about discrete rotational and vibrational energy states according to a Boltzmann distribution.
  • a temperature dependence of ⁇ 13 03 ⁇ 4 can affect the long term stability and sensitivity of diode laser based isotopic measurements of carbon dioxide, [references 2 - 6 ] 13 C0 2 and 12 C0 2 absorption lines with near equal ground state energies can be useful in attaining relative temperature insensitivity for isotopic ratio measurements.
  • VCSELs Vertical cavity surface emitting lasers
  • VCSELs have been shown to attain scan ranges of 10 to 15 cm “1 . These have been used to give rise to rugged, high precision field instruments as exemplified by a laser hygrometer manufactured by Southwest Sciences, Inc and a handheld methane leak detector manufactured by the Southern Cross Company. Accordingly, for certain apparatuses for use in the invention, VCSELs can be used that may be scanned over the desired spectral wavelengths, at a useful scan rate in the context of an overall testing apparatus as to give rise to some or all of the desired benefits of the present invention. In some embodiments, the VCSEL devices are caused to scan in the kilohertz scan rate or greater over approximately 10 cm "1 ranges.
  • Suitable laser sources may also be formed from a plurality, usually a pair of laser emitters. Such emitters may be fabricated to emit at one of the preferred wavelengths of a wavelength pair.
  • VCSEL devices useful in the invention may be ordered from Vertilas GmbH of Germany and can also be made by other sources of laser emitters.
  • wavelengths will confer either improved accuracy, improved temperature stability or another of the desirable properties set forth herein to the measurement of CO 2 isotopic ratios.
  • preferred wavelengths will be within 0.5 of a nanometer of the recited values.
  • the apparatuses useful with the present invention include a sample container for holding the gas sample, which container is configured to provide a relatively long light path through the sample by way of mirrors.
  • One or more signal detectors are included as is control circuitry for controlling the laser and for collecting and manipulating the output signal from the detector or detectors.
  • All such components are preferably sufficiently rugged as to permit the deployment of the devices outside of a laboratory and even in a hand held context.
  • the present apparatuses are also useful in a system or kit.
  • Components of the system or kit may include sample collection containers, such as gas tight bags, preferably ones featuring injection ports, syringes, and other items which facilitate sample collection and transfer to the sample chamber of the apparatus.
  • sample collection elements may assume different configurations depending upon the source of the gas to be sampled. Thus, the same may, for example, be useful for collecting breath of a subject, such as when sampling headspace gases from the stomach of a subject.
  • Portable devices and systems are known having a general arrangement of elements suitable for us in some of the embodiments of the present invention. For example, the '96 Hawk hand-held methane leak detector system sold by Southern Cross Corp.
  • FIG. 1 depicts certain aspects of one device that can be used with the presenting invention.
  • a CO 2 optical absorption measurement device is depicted 100, which comprises a diode laser source, mirrors 114, and gas sample chamber 104. Taken together, these form an optical path in conjunction with preferred reflective surfaces inside the sample chamber, not shown. The optical path, which is effectively many times longer than the physical length of the chamber, permits the enhanced absorption of laser light by gas samples in the chamber.
  • One or more gas pumps, 112 are conveniently included to transport gas sample into and out of the sample chamber which may, likewise, be provided with one or more pressure gauges.
  • a reference gas chamber, 106 is also employed together with mirrors, 114 for directing laser light through the reference gas chamber 106.
  • the light paths through the sample and reference chambers are directed to one or more detectors, 108 for assessing the intensity of laser light.
  • Processor or processors in control module, 1 10 determine the amount of absorption of incident laser light by the sample in the sample chamber, by reference to the reference sample in the reference chamber. This determination may be performed by routine software of firmware, either on board the device or external to it.
  • electrical connections, 1 16 are provided enabling either signals or processed data from the device to be ported to external display or data collection and manipulation devices.
  • controller which may be on board the instrument or external to it, may be a general purpose digital computational device or a special purpose digital or digital - analog device or devices. Control by the controller may be of, for example, power supplies for the laser, detector, gas sample pump, processors and other components.
  • a gas sample suspected of containing carbon dioxide is placed into the sample chamber of the devices of the invention.
  • the laser light source or sources is then caused to transit the sample chamber, preferably via a recurring pathway so as to increase the overall path length and improve the measurement sensitivity.
  • the light source is then directed to one or more sensors and the sensor readings interpreted to give rise to a value for wavelength absorption by the sample.
  • the methodologies for making this determination are well known in the art, and include, for example, direct absorption spectroscopy, wavelength modulation spectroscopy, cavity ringdown spectroscopy, and other alternatives
  • values for the carbon 12 and carbon 13 isotopes in the carbon dioxide sample become known. Perforce, their ratio may be calculated.
  • a reference gas sample is provided and the same irradiated, detected and the signal interpreted. The data thus obtained is used to standardize the data arising from irradiation of the sample chamber.
  • the mechanics of the apparatus including the supply of power to the laser light source or sources, to the detectors and to any data storage, presentation and manipulation elements is preferably under the control of a controller, whether digital or analog.
  • a digital computer may also or in addition be used. Such computer may be on board or connected via a control interface.
  • WMS wavelength modulation spectroscopy
  • WMS is preferred to direct absorption spectroscopy for use in the present invention, although direct measurement may be used if desired.
  • direct absorbance measurements the laser current is ramped so that the wavelength output is repeatedly scanned across a gas absorption line and the spectra generated are co-averaged. Analysis of direct absorption spectra involves detecting small changes on a large detector signal. For very low concentration changes this is problematic.
  • a small high-frequency sinusoidal modulation is superimposed on the diode laser current ramp. This current modulation produces a modulation of the laser wavelength at the same high frequency. Absorption by the target gas converts the wavelength modulation to an amplitude modulation of the laser intensity incident on the detector, adding AC components to the detector photocurrent.
  • the detector photocurrent is demodulated at twice the modulation frequency, 2f detection. This selectively amplifies only the AC components (a zero background measurement) and shifts the measurement from near DC to higher frequencies where laser noise is reduced. Spectral noise is greatly reduced by performing signal detection at frequencies (>10 kHz) high enough to avoid fluctuations in the laser output power, laser excess (l/J) noise.
  • WMS has measured absorbances as low as 1 x 10 ⁇ 7 , which is near the detector noise limit.
  • background artifacts typically limit the minimum detectable absorbance a m izie to 1 10 "5 s "1 ⁇ 2 .
  • the value for a m i n can be improved by longer time averaging of the 2 signal with the improvement scaling as t 1 ⁇ 2 for periods of 100 to 300 seconds.
  • the 13 C0 2 and 12 C0 2 absorption line pairs described herein give rise to relatively temperature insensitive 5 13 C0 2 isotopic ratio determinations in gas samples are separated by several absorption lines that do not need to be measured.
  • the electronics is caused to operate the laser in a jump scan fashion. This is illustrated in Figure 2.
  • the laser current scan is programmed to have a discontinuity that will rapidly change the wavelength.
  • the first few data points after the jump are preferably not used, as the laser wavelength may not be stable immediately after the current jump.
  • VCSELs used in the present invention may be operated in this way even with four current jumps in order to measure five different absorption lines simultaneously with no undue reduction in sensitivity.
  • compositions for oral administration or inhalation, i.e., pulmonary, administration are as otherwise described herein.
  • Oral compositions include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.
  • compositions for pulmonary administration include a pharmaceutically acceptable carrier, additive or excipient, as well as a propellant and optionally, a solvent and/or a dispersant to facilitate pulmonary delivery to the subject.
  • Sterile compositions for injection can be prepared according to methods known in the art.

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Abstract

La présente invention concerne des procédés de détermination de la localisation d'une charge bactérienne dans les poumons d'un sujet.
PCT/US2013/074629 2012-12-12 2013-12-12 Détermination de la localisation d'une charge bactérienne dans les poumons Ceased WO2014093604A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR112015013826A BR112015013826A2 (pt) 2012-12-12 2013-12-12 método para determinar a presença ou ausência e localização de uma carga bacteriana no sistema respiratório de um indivíduo
HK16102961.3A HK1215069A1 (zh) 2012-12-12 2013-12-12 肺中的細菌負荷位置的確定
CN201380064969.9A CN104903725A (zh) 2012-12-12 2013-12-12 肺中的细菌负荷位置的确定
EP13814762.4A EP2932262A1 (fr) 2012-12-12 2013-12-12 Détermination de la localisation d'une charge bactérienne dans les poumons
RU2015128043A RU2015128043A (ru) 2012-12-12 2013-12-12 Определение местоположения бактериальной нагрузки в легких
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Publication number Priority date Publication date Assignee Title
RU2709435C2 (ru) * 2015-06-11 2019-12-17 Нео Мониторс Ас Датчик дыма
DE102022109757A1 (de) 2022-04-22 2023-10-26 Innovative Sensor Technology Ist Ag Verfahren, System und Messgerät zum Ermitteln eines Vorhandenseins von lebenden Bakterien in einer Probe

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BR112015013826A2 (pt) 2017-07-11
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